Project Summary: Clinicians are placed in a quandary when treating the 750,000 new cases of pediatric mild traumatic brain injury (pmTBI) that occur each year. Specifically, the etiology (e.g., diffuse brain injury, disrupted cerebral blood flow, or psychological factors) of post-concussive symptoms (PCS), the long-term impact of pmTBI on academic and social functioning, and the effect of age-at-injury are all currently unknown. The trajectory of neurodevelopment varies as a function of age, pubertal stage and biological sex, suggesting that findings relevant for one group of children (e.g., male adolescents, the typical sample derived in most studies of pmTBI) may not directly translate to children in another developmental phase. Age interacts with recovery in animal models, potentially as a result of differences in plasticity (early vulnerability vs. early plasticity) or due to critical periods. However, empirical evidence in the human literature is currently mixed as a result of heterogeneous sampling strategies that conflate injury severity (i.e., mild through severe TBI) and overlapping neurodevelopment periods. There is not a single study examining clinical outcomes and diffuse injury mechanisms for pmTBI occurring during middle childhood (8-12 years old [y.o.]). The parent grant and competing revision address this critical knowledge gap by collecting longitudinal (approximately 1 week, 4 months and 1 year post-injury) neuroimaging and clinical data in two neurodevelopmentally distinct pmTBI patient cohorts (8-12 y.o. = competing revision [N = 150]; 13-18 y.o. = parent grant [N = 150]) and age- and sex-matched healthy controls (HC; N = 250). This study specifically evaluates potential mechanisms of action for diffuse white matter (WM) and gray matter (GM) injuries in pmTBI (Aim 1) and identifies the role of these diffuse injuries, pre-morbid and age-at-injury factors on clinical outcomes (Aim 2). Biological factors such as sex, pubertal stage and the presence of structural lesions are carefully considered in the analytic plan to increase rigor. Data collected in the first 15 months of the parent award demonstrates increased PCS, objective cognitive deficits and diffuse injuries in semi-acute adolescent pmTBI (N=64) compared to matched HC (N=48). We are currently ahead of our originally proposed enrollment goals in spite of the shortened first year and reduced budget. Importantly, our new preliminary data suggest a pattern in which self-reported PCS is greater during middle childhood, but both objective testing and markers of diffuse injuries are greater for adolescents. Based on these data, we hypothesize that adolescent pmTBI will exhibit greater diffuse injuries and worse performance on objective clinical measures, with less evidence of recovery than middle childhood pmTBI, who will report more PCS. The competing revision will use identical clinical, imaging (multiband echo- planar imaging, multi-shell high angular resolution diffusion imaging sequence, cerebral vascular reactivity and p-CASL) and innovative analyses as the parent grant, building upon existing infrastructure for patient recruitment, patient assessment, analyses and data dissemination. These independent measures of diffuse injury will provide critical information on how WM and deep GM structures are affected by trauma above and beyond any structural findings, providing mechanisms of target engagement for future therapeutic trials. The public health significance of the current application is multifold. First, the current study will provide evidence- based data on diffuse brain injuries following pmTBI occurring at two separate critical stages of brain maturation and their relationship to clinical outcomes over a one-year period. This represents a major advance for the field given the current lack of a gold standard for diagnosing injury and the limited scientific understanding of prognostic indicators of pmTBI. The application also represents the first step towards understanding why some children do not recover from their injuries, and will allow clinicians to make more informed decisions regarding when it is safe to return to physical and academic activity following pmTBI based on the patient?s developmental stage.